Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4](O)(=[O:6])C.C(O)(=O)C.IC1C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1.Cl>CO>[CH3:4][O:6][CH:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: CC(=O)O
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: CO
Product: COC(=O)C(OC)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 15.6 %

Procedure:
A 28% solution of sodium methoxide in methanol (12.8 g) and iodobenzene diacetate (7.15 g) were added to a solution of methyl 4-methoxyphenylacetate (4.0 g) in methanol (60 mL), and the reaction solution was stirred at room temperature for five days. 1 N hydrochloric acid (67 ml) was added dropwise to the reaction solution under ice-cooling, and methanol was evaporated from the reaction solution under reduced pressure. Ethyl acetate was added to the remaining aqueous layer, and the organic layer was separated. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to obtain 725 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][CH:2]([CH2:26][CH2:27][C@H:28]([N:31]([CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:29][OH:30])[CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:7][C:8]([O:10][CH3:11])=[O:9]>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:31]([CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:28]([CH2:29][OH:30])[CH2:27][CH2:26][CH:2]([F:1])[CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:7][C:8]([O:10][CH3:11])=[O:9])(=[O:33])=[O:34])=[CH:40][CH:39]=1
Reactant: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A solution of the material from Step 14 (45 mg, 0.065 mmol) in (1:1) in ethyl acetate-ethanol (1 mL) was degassed with nitrogen, then 20% palladium hydroxide on carbon (4.6 mg, 0.007 mmol) was added. The reaction mixture was stirred under hydrogen (1 atm) for 3 hours. The reaction mixture was filtered through celite and washed with dichloromethane to afford 30 mg of the title compound. 1H NMR (DMSO-d6): δ 8.17 (d, J=6.98 Hz, 1H), 7.46-7.38 (m, 3H), 7.35-7.22 (m, 6H), 7.23-7.10 (m, 4H), 6.60 (dd, J=8.50, 3.17 Hz, 2H), 5.94 (s, 2H), 5.03-4.94 (m, 1H), 4.71-4.64 (m, 1H), 4.26 (d, J=11.45 Hz, 1H), 3.94-3.66 (m, 1H), 3.55-3.39 (m, 1H), 3.42 (s, 3H), 3.29-3.22 (m, 2H), 3.13-2.77 (m, 4H), 1.67-1.01 (m, 7H), 0.84 (dd, J=6.31, 3.38 Hz, 6H). The mixture of diastereomers was separated by SFC (AD-H, 4.6×250 mm, 30% i-PrOH in CO2, 2.4 mL/min, 100 bar, 40° C.
Reaction SMILES: C(OC(N(CC(O)=O)C[C:13]1[CH:18]=[C:17](F)[C:16](F)=[CH:15][C:14]=1[NH:21]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([O-:37])=[O:36].[C:14]1([NH3+:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+]c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of {benzyloxy carbonyl-(2-tert-butoxycarbonylamino-4,5-difluoro-benzyl)-amino]-acetic acid} (4.76 g, 10.56 mmol) in dry DCM (40 mL) was added trifluoroacetic acid (14.35 mL, 3 mL/mmol) at 0° C. The reaction mixture was stirred at r.t. for 2 h under argon. After completion of the reaction as confirmed by TLC, the reaction mixture was evaporated in vacuo to remove excess of solvent and trifluoroacetic acid. The remaining were removed under vacuo and 2-[(benzyloxycarbonyl-carboxymethyl-amino)-methyl]-4,5-difluoro, phenyl-ammonium trifluoroacetate (4.75 g, 97%) was obtained as thick brown jelly which was used as such without any further purification for the next step.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50]>O1CCCC1.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:19])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
A solution of 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid (0.43 g, 1.31 mmol) and carbonyldiimidazole (0.42 g, 2.62 mmol) in anhydrous tetrahydrofuran (22 mL) was refluxed under nitrogen for 30 min. The reaction mixture was cooled to ambient temperature and treated with 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 3.93 mmol) and methylsulfonamide (0.54 g, 3.93 mmol). The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ethyl acetate (60 mL), washed with 1 M aqueous hydrochloric acid (2×30 mL) and brine (50 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 30% ethyl acetate (containing 0.2% acetic acid) in hexanes to afford the title compound as a white solid (0.31 g, 58%); 1H NMR (300 MHz, DMSO-d6) δ 12.01 (br s, 1H), 8.47 (d, J=2.5 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 3.93 (s, 2H), 3.33 (s, 3H), 2.07-1.98 (m, 1H), 1.97-1.90 (m, 3H), 1.72-1.56 (m, 12 H), 0.98-0.90 (m, 2H), 0.76-0.70 (m, 2H); MS (ES+) m/z: 405.2 (M+H).
Reaction SMILES: [CH2:1](OC(C1SCCSC=1CCC)=O)[CH3:2].[CH2:15]([O:17][C:18]([C:20]1[S:25](=[O:27])(=[O:26])[CH2:24][CH2:23][S:22](=[O:29])(=[O:28])[C:21]=1[CH2:30][CH2:31][CH3:32])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[S:25](=[O:26])(=[O:27])[CH2:24][CH2:23][S:22](=[O:28])(=[O:29])[C:21]=1[CH2:30][CH2:31][CH3:32])=[O:19])[CH2:16][CH2:1][CH3:2]
Reactant: CCCC1=C(C(=O)OCC)SCCS1
Reactant: CCCC1=C(C(=O)OCC)S(=O)(=O)CCS1(=O)=O
Product: CCCCOC(=O)C1=C(CCC)S(=O)(=O)CCS1(=O)=O

Procedure:
By following substantially the procedure of Example 1, Step C, 3-ethoxycarbonyl-2-n-propyl-5,6-dihydro-1,4-dithiin (9.0 g.) yields 8.15 g. of 3-ethoxycarbonyl-2-n-propyl-5,6-dihydro-1,4-dithiin-1,1,4,4-tetroxide 73.5°-74.5° C.
Reaction SMILES: [BrH:1].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][CH2:6]2.[CH:13]([O-])=O.[Na+].C=O>C(O)=O>[BrH:1].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][N:7]([CH3:13])[CH2:6]2
Reactant: Oc1cc2c(cc1O)CNC2
Reactant: O=C[O-]
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1Cc2cc(O)c(O)cc2C1
Temperature: 80 °C
Yield: 72.3 %

Procedure:
15.39 g (66 mmol) of 5,6-dihydroxyisoindoline hydrobromide and 4.48 g (66 mmol) of sodium formate were dissolved in 100 ml of a 50% formic acid aqueous solution, and then 5.17 ml (70 mmol) of 37% formalin was added thereto. The mixture was heated at 80° C. for 4 hours. Then, the reaction solvent was distilled off under reduced pressure, and 200 ml of 23% hydrobromic acid was added to the residue. The mixture was subjected to active carbon treatment. The filtrate was again evaporated under reduced pressure to dryness, and the crystalline residue was recrystallized from water to obtain 11.74 g (yield: 72.3%) of the above identified compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13].C([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)#C.[CH2:40](N(CC)CC)[CH3:41]>CN(C=O)C.CCOCC.[Cu]I>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:40]#[C:41][C:37]2[CH:36]=[CH:35][C:34]([C:29]3[CH:28]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:39][CH:38]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13]
Reactant: CCN(CC)CC
Reactant: C#Cc1ccccc1-c1ccccc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(C#Cc2ccc(-c3ccccc3)cc2)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Yield: 63 %

Procedure:
To a solution of 1.0 g (2.336 mmol) of the product of Example 202 in 7.5 mL of DMF was added 0.50 g (2.804 mmol) of ethynyl biphenyl, 0.033 g (0.047 mmol) of bis triphenylphosphine palladium(II) dichloride 4.4 mg of copper(I) iodide and 7.5 mL of triethylamine. The reaction was heated to 80° for 5 h and then diluted with ether. the organics were washed with water, 5% HCl solution and sodium bicarbonate solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel cluting with EtOAc/hexanes (1:3) to provide 0.777 g (63%) of the alkyne as a brown foam. Electrospray Mass Spec: 526.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC1(C)OB(/C=C/c2ccc(C=O)c(F)c2)OC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a mixture of (E)-2-fluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzaldehyde (0.61 g, 2.2 mmol) and morpholine (0.3 mL) in DCE (20 mL) was added NaBH(OAc)3 (636 mg, 3 mmol), followed by AcOH (0.5 mL). The resulting mixture was stirred for 2 h at rt. The reaction was quenched with sat. NaHCO3 (10 mL), H2O (10 mL), and extracted with EtOAc (2×30 mL). The solvents were removed in vacuo to afford the title compound as a white solid (0.72 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.12 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 6.99 (d, J=10.8 Hz, 1H), 5.98 (d, J=18.4 Hz, 1H), 3.55-3.45 (m, 4H), 3.36 (s, 2H), 2.33-2.23 (m, 4H), 1.14 (s, 12H); MS ESI 348.2 [M+H]+, calcd for [C19H27BFNO3+H]+ 348.2.
Reaction SMILES: [CH:1]([N:3]1[CH:7](C(O)=O)[CH2:6][S:5][CH:4]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl[C:30](=[CH2:33])[C:31]#[N:32]>ClCCl.O>[C:31]([C:30]1[CH:33]=[CH:1][N:3]2[C:7]=1[CH2:6][S:5][CH:4]2[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:32]
Reactant: O=CN1C(C(=O)O)CSC1c1cccnc1
Reactant: C=C(Cl)C#N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccn2c1CSC2c1cccnc1
Yield: 74.4 %

Procedure:
3-Formyl-2-(3-pyridyl)-4-thiazolidinecarboxylic acid (10 g) is suspended in dichloromethane (15 cc) in a 50 cc three-necked flask equipped with a condenser, a dropping funnel, a magnetic stirrer, a thermometer and a gas-holder. Then triethylamine (4.8 g) is added at 20° C. A homogeneous colourless solution is obtained. This solution is added dropwise in the course of 50 minutes and at 25° C. to a stirred mixture of methanesulphonyl chloride (5.29 g) and dichloromethane (17 cc). 2-Chloroacrylonitrile (4.04 g) is then added quickly, followed at 20°-35° C. and over the course of one hour, by triethylamine (9.35 g) and dichloromethane (5 cc). The mixture is then refluxed for 50 minutes. After cooling, it is hydrolysed with water (12 cc). The organic phase is decanted and the aqueous phase extracted with dichloromethane. The organic extracts are combined and dried overnight over sodium sulphate. After filtering, the solvent is evaporated off under reduced pressure 20 mm Hg; 2.7 kPa) at 20° C. A crude product (9 g) is obtained, and is purified by chromatography on a column diameter 4.5 cm) containing silica (100 g) (0.063-0.2 mm), eluting with a mixture of ethyl acetate and dichloromethane. 7-Cyano-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole (7.10 g) is thereby obtained in the form of light beige-coloured crystals m.p. 108° C. (yield 82.5% relative to the acid used).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][OH:15].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: OCc1ccccc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1ccccc1-c1ccc(F)cc1
Temperature: 115 °C

Procedure:
To a mixture of 4-fluorophenylboronic acid (2.5 g, 13.4 mmol), 2-bromobenzyl alcohol (2.81 g, 20.1 mmol) and Pd(PPh3)4 (0.25 g, 0.216 mmol) in DME (20 mL) is added an aqueous solution of Na2CO3 (11.5 mL, 2.7 M, 31 mmol). The mixture is heated to 115° C. in sealed vessel overnight. The reaction is allowed to cool to room temperature and is diluted with EtOAc and water. The aqueous layer is extracted further with EtOAc (2×). The combined organic layers are washed with water, saturated NH4Cl, brine and dried over Na2SO4. After concentration, the resulting residue is purified by flash chromatography (hexane/CH2Cl2) to give (4′-fluorobiphenyl-2-yl)-methanol as oil. (cas #773871-75-3) 1H NMR (400 MHz, CDCl3) δ (ppm) 7.46-7.43 (m, 1H), 7.32-7.22 (m, 4H), 7.18-7.16 (m, 1H), 7.04-6.99 (m, 2H), 4.48 (d, J=5.5 Hz, 2H), 1.68 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>O1CCCC1.O>[Cl:11][C:12]1[N:17]=[C:16]([NH:10][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH3:9])[CH:15]=[CH:14][N:13]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Clc1ccnc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](Nc1ccnc(Cl)n1)c1ccc(F)cn1
Temperature: 55 °C
Yield: 10.1 %

Procedure:
A solution of (S)-1-(5-fluoropyridin-2-yl)ethanamine (prepared as described in WO2006/123113, 235 mg, 1.68 mmol) in tetrahydrofuran (2 mL) was added to a stirred solution of 2,4-dichloropyrimidine (250 mg, 1.68 mmol) in tetrahydrofuran (2 mL) at ambient temperature. A solution of triethylamine (0.23 mL, 1.68 mmol) in tetrahydrofuran (2 mL) was then added dropwise and the reaction mixture was heated overnight at 55° C. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (43 mg, 10%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:17]Br>ClCCl>[Br:17][CH:10]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-(2,4-dichlorophenyl)-3-oxopropanoate (3.95 g, 15.1 mmol) in dichloromethane (150 mL) was added a solution of bromine (0.935 mL, 18.2 mmol) in dichloromethane (20.0 mL) dropwise at 0° C. The solution was then stirred at room temperature for 1 hour. The reaction was quenched with 10% aqueous potassium carbonate solution, and then the layers were separated. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude oil was used directly in the next step (5.27 g, quantitative). LCMS: (AA) ES+, 341. 1H NMR (400 MHz, d1-chloroform) (2 sets of signals, keto and enol): 12.78 (s, 1H), 7.73-7.28 (m, 2 sets of 3H), 5.73 (s, 1H), 4.37 (q, J=7.28 Hz, 2H), 4.29 (q, J=7.28 Hz, 2H), 1.41 (t, J=7.03 Hz, 3H), 1.29 (t, J=7.03 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11](O)[C:10]2=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:29]=[C:30]([Cl:32])[CH:31]=1.O>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]2[CH2:37][CH2:36][N:35]([C@H:11]3[CH2:12][CH2:13][N:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)[C:10]3=[O:15])[CH2:34]2)[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: O=C1[C@H](O)CCN1c1cc(F)cc(F)c1
Reactant: Clc1cc(Cl)cc(C2CCNC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)cc(F)c1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
Synthesized according to General Procedure 10. To a solution of (R)-1-(3,5-difluorophenyl)-3-hydroxypyrrolidin-2-one (213 mg, 1.0 mmol) in DCM (0.7 mL) at −20° C. was added DIEA (259 mg, 348 μL, 2.0 mmol) followed by the dropwise addition of triflic anyhydride (282 mg, 168 μL, 1.0 mmol) and the reaction mixture was stirred at −20° C. for 45 min. A solution of 3-(3,5-dichlorophenyl)pyrrolidine (216 mg, 1.0 mmol) in DCM (0.7 mL) was added dropwise and the reaction mixture was stirred at −20° C. for 16 hours. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. Purification by silica gel chromatography (0-20% EtOAC in DCM) afforded (3′S)-3-(3,5-dichlorophenyl)-1′-(3,5-difluorophenyl)-1,3′-bipyrrolidin-2′-one as an oil that solidified upon standing (210 mg, 51%). 1H-NMR (400 MHz, CDCl3) 7.33-7.28 (m, 2H), 7.19-7.17 (m, 2H), 6.64-6.58 (m, 2H), 3.83-3.74 (m, 1H), 3.72 (dd, J=7.4, 8.7 Hz, 1H), 3.64-3.57 (m, 1H), 3.49-3.45 (m, 0.5H), 3.37-3.25 (m, 1.5H), 3.19 (m, 1H), 3.06-2.90 (m, 1.5H), 2.76 (dd, J=7.3, 9.0 Hz, 0.5H), 2.43-2.29 (m, 2H), 2.23-2.15 (m, 1H) and 1.94-1.85 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=411.3; tR=1.46 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:19]([C:20]([NH2:22])=[O:21])=[C:12]3[CH2:13][NH:14][C:15]4([CH2:18][CH2:17]4)[CH2:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.O>[C:23]([NH:27][C:28]([N:14]1[C:15]2([CH2:18][CH2:17]2)[CH2:16][N:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[C:19]([C:20]([NH2:22])=[O:21])=[C:12]2[CH2:13]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNC1(CC1)C2
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC12CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.3 %

Procedure:
To a solution of Intermediate 350H (30 mg, 0.094 mmol) in THF (2 mL) was added TEA (0.026 mL, 0.187 mmol) and tert-butyl isocyanate (0.022 mL, 0.187 mmol) and the resulting solution was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC to afford Compound 350 as an off-white solid (10 mg, 25%). HPLC retention times 9.363 min. and 13.023 min. (Methods A and F respectively). MS(ES): m/z=420 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.31, 2.16 Hz, 1H), 7.68 (ddd, J=8.63, 4.80, 2.20 Hz, 1H), 7.45 (t, J=9 Hz, 1H), 7.30 (br. s, 1H), 7.16 (br. s, 1H), 4.78 (br. s, 2H), 4.10 (br. s, 2H), 1.26 (s, 9H), 1.09 (s, 4H).
Reaction SMILES: [OH-].[Na+].Cl[C:4]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[C:10]([Cl:24])[CH:9]=1)=[CH:5]C=O.ClCCl>O.O1CCOCC1>[Cl:24][C:10]1[CH:9]=[C:8]([C:4]#[CH:5])[CH:13]=[CH:12][C:11]=1[CH:14]1[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]1
Reactant: CC1(C)CC(c2ccc(C(Cl)=CC=O)cc2Cl)CC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(C2CC(C)(C)CC(C)(C)C2)c(Cl)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
5.3 g of sodium hydroxide are dissolved in 150 ml of water under an inert atmosphere and with vigorous stirring. 80 ml of 1,4-dioxane are added and the mixture is refluxed. 15 g of 3-chloro-3-[3-chloro-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]propenal (compound IV.1) dissolved in 130 ml of 1,4-dioxane are added rapidly, and the reaction mixture is maintained at reflux for 1 hour. After cooling to room temperature, the reaction mixture is poured into a large volume of dichloromethane. The phases are separated after settling has taken place, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. Purification is carried out by chromatography on a column of silica gel, eluting with cyclohexane; yield: 80%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([C@H:24](O)[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.CCCCCC>ClCCl>[Br:1][C@H:24]([C:16]1[CH:15]=[C:14]([C:13]([F:28])([F:27])[F:12])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1)[CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: CSC
Solvent: ClCCl
Product: C[C@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
Under an argon atmosphere, a suspension of N-bromosuccinimide (103 mg, 0.58 mmol) in anhydrous dichloromethane (2.0 mL) was added dropwise with dimethyl sulfide (53 μL, 0.70 mmol) under ice cooling over 3 minutes. The mixture was added dropwise with a solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (100 mg, 0.39 mmol, >99.5% ee) in anhydrous dichloromethane (1 mL) at −20° C., and the mixture was stirred at room temperature for 6 hours. The reaction mixture was add with n-hexane, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent, n-hexane) to obtain 82 mg of (S)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.